Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2(O)[CH2:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>ClCCl>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1
Reactant: OC1(c2ccc(Br)cc2)CCC1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1(c2ccc(Br)cc2)CCC1
Temperature: 25 °C
Yield: 92.7 %

Procedure:
TBSOTf (360 μL, 1.57 mmol) was added to a 0° C. solution of 3-1 (235 mg, 1.04 mmol) and triethylamine (450 μL, 3.23 mmol) in dichloromethane (3 mL). The reaction was allowed to warm to room temperature and after 1 h, saturated NaHCO3 solution was added. The resulting mixture was extracted with ethyl acetate (3×30 mL) and the combined ethyl acetate solution was washed with brine. The solution was then dried (Na2SO4), filtered and evaporated. Purification by flash chromatography on silica gel (hexanes) gave 3-2 (329 mg, 93%).
Reaction SMILES: C=O.[Cl:3][C:4]1[CH:15]=[C:14]2[C:7]([NH:8][C:9]([CH2:16][CH3:17])=[C:10]2[CH2:11][CH2:12]N)=[CH:6][CH:5]=1.[C:18]([BH3-])#[N:19].[Na+].[C:22]([O-])([O-])=O.[K+].[K+]>CO.CC(O)=O>[Cl:3][C:4]1[CH:15]=[C:14]2[C:7]([NH:8][C:9]([CH2:16][CH3:17])=[C:10]2[CH2:11][CH2:12][N:19]([CH3:18])[CH3:22])=[CH:6][CH:5]=1
Reactant: [BH3-]C#N
Reactant: O=C([O-])[O-]
Reactant: CCc1[nH]c2ccc(Cl)cc2c1CCN
Agent: C=O
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCc1[nH]c2ccc(Cl)cc2c1CCN(C)C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
40% HCHO (0.95 mL) in MeOH (16 mL) was added dropwise to a stirred cooled (0° C.) solution of (5) (3.16 mmol), AcOH (0.47 mL) and sodium cyanoborohydride (0.35 g). The resulting mixture was allowed to stir at 25° C. for 2.5 h. A saturated aqueous solution of K2CO3 (5 mL) was added, MeOH was removed in vacuo and the aqueous phase was extracted with EtOAc. After drying over Na2SO4, the solvent was evaporated under reduced pressure to give a crude residue which was purified by filtration on silica gel.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].N1C=CC=CC=1.[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25].C(OCC)(=O)C>O1CCCC1>[CH2:11]([O:10][C:8]([C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:2]=1[NH:1][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][Br:19])=[O:9])[CH3:12]
Reactant: O=C(Cl)CCCCBr
Reactant: CCOC(=O)C1=C(N)CCCC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(NC(=O)CCCCBr)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
In 150 ml of tetrahydrofuran, 42.3 g of ethyl 2-aminocyclohex-1-enecarboxylate as synthesized in above Step 7-1-B was dissolved, to which 40 g of pyridine was added, and then 5-bromovaleryl chloride was dropped thereinto under cooling with ice. Stirring the system for an overnight at room temperature, ethyl acetate was added, followed by washing with saturated aqueous sodium hydrogencarbonate solution, 10% aqueous citric acid and saturated brine, and drying over anhydrous magnesium sulfate. Concentrating the solvent under reduced pressure, the residue was purified on silica gel column chromatography (n-hexane:ethyl acetate=8:1) to provide 76.6 g (92%) of 2-(5-bromopentanoylamino)-cyclohex-1-enecarboxylic acid ethyl ester.
Reaction SMILES: C(O[C@H:5]1[O:27][C@@H:26]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:6]1[O:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)C.[Br:38][C:39]1[C:40](=[O:46])[NH:41][C:42](=[O:45])[NH:43][CH:44]=1.C[Si](N[Si](C)(C)C)(C)C.C[Si](Cl)(C)C>CC#N>[C:8]([O:7][C@H:6]1[C@@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C@H:26]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[O:27][C@@H:5]1[N:43]1[CH:44]=[C:39]([Br:38])[C:40](=[O:46])[NH:41][C:42]1=[O:45])(=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=c1[nH]cc(Br)c(=O)[nH]1
Reactant: CC(=O)O[C@H]1O[C@@H](COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CC#N
Product: O=C(OC[C@@H]1O[C@H](n2cc(Br)c(=O)[nH]c2=O)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
A solution of 1-O-acetyl-2,3,5-tri-O-benzoyl-β-L-ribofuranose (2.3 g, 4.55 mmol) in CH3CN (30 mL) was added to silylated 5-bromouracil [generated from 5-bromouracil (2.2 g, 14.3 mmol), HMDS (10 mL), and TMSCl (0.2 mL) by heating for 2 h at 80° C. followed by evaporation of the solvents], and the mixture cooled to 0° C. 1 M SnCl4 (13.6 mL) was added drop-wise, and the mixture stirred for 2 h at room temperature. The mixture was diluted with CHCl3 (100 mL) and quenched with cold saturated NaHCO3. The mixture was filtered over a Celite pad, and the organic phase separated, dried (MgSO4), and evaporated to give a white solid. The solid was washed with cold EtOAc and crystallized from EtOAc in hexanes to give the title compound (2.85 g, 98%) as a white crystals. 1H-NMR (CDCl3) δ 8.06 (1H, br s, NH), 8.06-7.29 (15H, m, Bz) 7.68 (1H, s, H-6), 6.29 (1H, d, H-1′, J=6 Hz), 5.81 (1H, m, H-3′), 5.65 (1H, t, H-2′, J=6 Hz), 4.77-4.62 (3H, m, H-4′, H-5′a, and 5′b).
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=4)[N:17]=3)[NH:12][CH:11]=2)=[O:9])[CH2:3]1.[BH3-][C:30]#N.[Na+].C=O>CO.CC(O)=O>[CH3:30][N:2]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=4)[N:17]=3)[NH:12][CH:11]=2)=[O:9])[CH2:3]1
Reactant: [BH3-]C#N
Reactant: COc1ccc(-c2cnc3[nH]cc(C(=O)NC4CCNC4)c3n2)cc1OC
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(-c2cnc3[nH]cc(C(=O)NC4CCN(C)C4)c3n2)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
To a mixture of 2-(3,4-dimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid pyrrolidin-3-ylamide hydrochloride (12 mg, 0.03 mmol) in MeOH (0.5 mL) was added NaBH3CN (15 mg, 0.23 mmol). A solution of HOAc (1 drop) in MeOH (1 mL) was prepared and 2 drops of this solution was added to the reaction mixture so that the pH ˜4. Aqueous CH2O (37%, 25 μL, 0.34 mmol) was added to the reaction mixture which was then stirred at room temperature for 2 h, partitioned between saturated Na2CO3 and CH2Cl2. The aqueous layer was extracted with CH2Cl2 and the combined organic phases were dried (Na2SO4) and concentrated to give a pale yellow solid. The crude product was washed with Et2O to afford 11 mg (100%) of 2-(3,4-dimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-methyl-pyrrolidin-3-yl)-amide as a yellow powder. MP 193-194° C., M+H 382.
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C(Cl)CCl.C1C=C2N=NN(O)C2=CC=1.O.O/[N:30]=[C:31](\[NH2:50])/[C:32]1[CH:37]=[CH:36][C:35]([C@H:38]2[CH2:49][CH2:48][C:40]3([NH:44][C:43](=[O:45])[N:42]([CH3:46])[C:41]3=[O:47])[CH2:39]2)=[CH:34][CH:33]=1>CN(C=O)C>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]2[O:11][N:30]=[C:31]([C:32]3[CH:33]=[CH:34][C:35]([C@H:38]4[CH2:49][CH2:48][C:40]5([NH:44][C:43](=[O:45])[N:42]([CH3:46])[C:41]5=[O:47])[CH2:39]4)=[CH:36][CH:37]=3)[N:50]=2)=[CH:12][CH:13]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: CN1C(=O)NC2(CC[C@H](c3ccc(/C(N)=N/O)cc3)C2)C1=O
Reactant: CC(C)Cc1ccc(C(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: CC(C)Cc1ccc(-c2nc(-c3ccc([C@H]4CCC5(C4)NC(=O)N(C)C5=O)cc3)no2)cc1
Temperature: 140 °C
Yield: 21 %

Procedure:
A solution of 4-isobutylbenzoic acid (0.130 g, 0.728 mmol), EDC (0.139 g, 0.728 mmol) and HOBt hydrate (0.111 g, 0.728 mmol) in DMF (1.0 ml) was stirred at ambient temperature for 1-1.5 hours. To the mixture was added (Z)-N′-hydroxy-4-{(7S)-3-methyl-2,4-dioxo-1,3-diazaspiro[4.4]nonan-7-yl}benzimidamide (0.200 g, 0.662 mmol) as solution in 1.0 ml DMF at ambient temperature. The resulting mixture was heated to about 140° C. for additional 2 hours. Solvent was removed in vacuo. The crude product was purified on a Prep HPLC system using 20-99% 50 mM NH4OAc buffer in acetonitrile at 81 mL/min to afford (7S)-7-(4-(5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl)phenyl)-3-methyl-1,3-diazaspiro[4.4]nonane-2,4-dione (0.062 g, 0.139 mmol) as light brown solid.
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].Cl[S:8]([C:11]1[CH:12]=[CH:13][C:14]([F:20])=[C:15]([CH:19]=1)[C:16]([OH:18])=[O:17])(=[O:10])=[O:9].[CH3:21]C(C)=O>O.C(=O)([O-])[O-].[Na+].[Na+]>[F:20][C:14]1[CH:13]=[CH:12][C:11]([S:8]([CH3:21])(=[O:10])=[O:9])=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]
Reactant: CC(C)=O
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1F
Agent: O=C([O-])[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Temperature: 60 °C

Procedure:
A solution of sodium sulphite (10.6 g) in water (20 mL) was warmed to 80° C. and slowly added with stirring to a solution of 5-chlorosulfonyl-2-fluorobenzoic acid (10 g) in acetone (10 mL), saturated aqueous sodium carbonate being added simultaneously for keeping the liquid in alkaline. The mixture was stirred at 60° C. for one and a half hours, and concentrated in vacuo. The residue was suspended in a mixture of ethanol (20 mL) and water (20 mL), then iodomethane (2.61 mL) was added to the mixture. The reaction mixture was stirred for 2 hours at 60° C. and for an hour at 100° C. After cooling to ambient temperature, ethanol was removed in vacuo. The resultant aqueous solution was acidified with concentrated hydrochloric acid. The aqueous solution was extracted with chloroform (3 times), and the combined organic layer was dried over magnesium sulfate. After evaporation of the solvent, the residual oil was crystallized from ethanol to give 2-fluoro-5-methanesulfonylbenzoic acid (563.6 mg) as a colorless solid.
Reaction SMILES: [CH:1]1([CH:6]([O:19][CH3:20])[C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=2[CH2:17]O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Br)(Br)(Br)[Br:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:22][CH2:17][C:8]1[CH:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:11]=[CH:12][C:7]=1[C@H:6]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[O:19][CH3:20]
Reactant: BrC(Br)(Br)Br
Reactant: COC(c1ccc(C(F)(F)F)cc1CO)C1CCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CO[C@H](c1ccc(C(F)(F)F)cc1CBr)C1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of (2-(cyclopentyl(methoxy)methyl)-5-(trifluoromethyl)phenyl)methanol (enatiomer 2 from the chiral separation of the racemate in STEP C, 23.1 mg, 0.080 mmol) and carbon tetrabromide (34.5 mg, 0.10 mmol) in methylene chloride (0.5 mL) at room temperature was added triphenyl phosphine (27.3 mg, 0.10 mmol). The mixture was stirred at room temperature overnight. Solvent was removed and the residue was purified by chromatography over 12+S Biotage silica column (eluted with 0-20-30% ethyl acetate in heptane) to afford the title compound (23.1 mg, 82%). 1H NMR (400 MHz, CDCl3) δ ppm 1.15-1.27 (m, 1H) 1.34-1.44 (m, 1H) 1.44-1.72 (m, 5H) 1.78-1.87 (m, 1H) 2.16-2.26 (m, 1H) 3.21 (s, 3H) 4.32 (d, J=7.88 Hz, 1H) 4.57 (d, J=10.37 Hz, 1H) 4.67 (d, J=10.37 Hz, 1H) 7.49-7.59 (m, 2H) 7.61 (s, 1H). The other enantiomer of the title compound was prepared in the same manner using enantiomer 1 from the chiral separation of the racemate in STEP C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[C:11]([Cl:21])[CH:10]=1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[C:11]([Cl:21])[CH:10]=1
Reactant: Cc1cc(CNC(=O)OC(C)(C)C)cc(Cl)c1NS(C)(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(CN)cc(Cl)c1NS(C)(=O)=O
Reaction time: 12 h
Yield: 145.8 %

Procedure:
(3-Chloro-4-methanesulfonylamino-5-methyl-benzyl)-carbamic acid t-butyl ester (153.8 mg, 0.44 mmol) and CF3COOH (5˜6 drops) were added into methylene chloride. The mixture was stirred for 12 hrs. A reaction solvent was concentrated in vacuo to yield syrup (159.6 mg, 100%).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])=[CH:3][CH:2]=1.[CH3:16][O:17][C:18](=[O:31])[C@@H:19]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)[NH:20]1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:16][O:17][C:18](=[O:31])[C@@H:19]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)[N:20]1[C:13](=[O:15])[CH2:12][NH:11][C:9]([O:8][CH2:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)=[O:10]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: COC(=O)[C@@H]1CCC(c2cccc(O)c2)N1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1CCC(c2cccc(O)c2)N1C(=O)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.6 g of Z-glycine dissolved in dichloromethane is coupled with 0.83 g of 5-(meta-hydroxyphenyl)proline methyl ester in the presence of 2.06 g of PyBrOP and 2.6 ml of diisopropylethylamine. After stirring for 4 hours at room temperature, the organic phase is washed (sodium hydrogen carbonate, water, citric acid, water), dried over sodium sulphate, filtered and evaporated to dryness. The oily residue is chromatographed on silica gel (n-hexane/ethyl acetate. 4:6). A white solid corresponding to the expected product is obtained.
Reaction SMILES: [O:1]=[C:2]1[NH:11][CH:10]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[S:20]([CH3:23])(=[O:22])=[O:21])[C:9]2[C:8](=[O:24])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:42][CH:43]1[CH2:46][O:45][CH2:44]1>CN(C=O)C.O>[CH3:23][S:20]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:12]=1[CH:10]1[C:9]2[C:8](=[O:24])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:34])[F:32])[CH:26]=2)[C:2](=[O:1])[N:11]1[CH2:42][CH:43]1[CH2:46][O:45][CH2:44]1)[C:16]#[N:17])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Reactant: BrCC1COC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cc(C#N)ccc1C1C2=C(CCCC2=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1CC1COC1
Temperature: 50 °C

Procedure:
To a solution of 4-[2,5-dioxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4,5,6,7,8-octahydro-quinazolin-4-yl]-3-methanesulfonyl-benzonitrile (INTERMEDIATE 18, 150 mg, 0.28 mmol) in DMF (3.0 mL) is added cesium carbonate (178 mg, 0.55 mmol) and 3-bromomethyl-oxetane (83 mg, 0.55 mmol) and the mixture is stirred at 50° C. over night. The reaction mixture is diluted with DMF and water and purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 35.5 mg; ESI mass spectrum [M+H]+=560; Retention time HPLC: 1.04 min (Z018_S04).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][C:3]=1[C:9]([O:11][CH3:12])=[O:10].C(N(CC)CC)C.[NH2:20][NH2:21].O>C(O)C>[Cl:8][C:6]1[CH:7]=[C:2]([NH:20][NH2:21])[C:3]([C:9]([O:11][CH3:12])=[O:10])=[CH:4][N:5]=1
Reactant: NN
Reactant: COC(=O)c1cnc(Cl)cc1Cl
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(Cl)cc1NN
Temperature: 25 °C

Procedure:
Into a 20-L 4-necked round-bottom flask was placed methyl 4,6-dichloropyridine-3-carboxylate (1200 g, 5.82 mol), ethanol (10 L), and triethylamine (1182 g, 11.68 mol). NH2NH2.H2O (351 g, 7.02 mol) was then added drop-wise to the reaction mixture at 0° C. The resulting solution was heated to reflux for 1 h. The reaction mixture was cooled to room temperature. The solid was collected by filtration to give methyl 6-chloro-4-hydrazinylnicotinate, which was carried onto the next step without further purification.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([C:13](=[O:15])[CH3:14])=[CH:11][C:10]([Cl:16])=[C:9]([CH3:17])[C:8]=1[C:18]#[N:19])(=O)=O.[F:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1.O.N#N>C1(C)C=CC=CC=1.[Na].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:13]([C:12]1[CH:11]=[C:10]([Cl:16])[C:9]([CH3:17])=[C:8]([C:18]#[N:19])[C:7]=1[C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([F:22])[CH:28]=1)(=[O:15])[CH3:14]
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(=O)c1cc(Cl)c(C)c(C#N)c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)c1cc(Cl)c(C)c(C#N)c1-c1cccc(F)c1
Temperature: 80 °C
Yield: 98.5 %

Procedure:
A biphasic solution of 6-acetyl-4-chloro-2-cyano-3-methylphenyl trifluoromethanesulfonate (2.537 g, 7.425 mmol) and (3-fluorophenyl)boronic acid (1.56 g, 11.1 mmol) in toluene (70 mL) and 0.8 M sodium hydrogenecarbonate in water (70 mL, 50 mmol) was bubbled with N2 to degas. Tetrakis(triphenylphosphine)palladium(0) (0.429 g, 0.371 mmol) was added. The mixture was degassed with N2 for an additional 5 minutes and then heated at 80° C. for 2 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate. The layers were separated and the aq. layer was extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to a dark solid. The material was dissolved in CHCl3 and was purified on silica gel column, eluting with 0 to 40% ethyl acetate in hexane, to give the desired product (2.105 g, 99%). LCMS calculated for C16H12ClFNO (M+H)+: m/z=288.1; Found: 288.1.
Reaction SMILES: [OH:1][CH:2]1[C:7]([O:10][CH3:11])([O:8][CH3:9])[CH2:6][CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1.[H-].[Na+].Cl[CH2:22][C:23]([CH3:25])=[CH2:24]>CN(C=O)C>[CH3:11][O:10][C:7]1([O:8][CH3:9])[CH2:6][CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3][CH:2]1[O:1][CH2:24][C:23]([CH3:25])=[CH2:22]
Reactant: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1O
Reactant: C=C(C)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)COC1CN(C(=O)OC(C)(C)C)CCC1(OC)OC
Yield: 76.9 %

Procedure:
The same operation as in Example (90a) was performed using tert-butyl 3-hydroxy-4,4-dimethoxypiperidine-1-carboxylate (5.2 g, 20 mmol), sodium hydride (55% content, 1.31 g, 30 mmol), 3-chloro-2-methyl-1-propene (3.63 g, 40 mmol) and DMF (50 mL). The residue was purified by column chromatography (elution solvent: hexane/ethyl acetate=10/1, 4/1, 2/1) to obtain 4.85 g of the title compound as a colorless oily substance (77%).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH:13]3[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]3)[CH2:9]2)=[CH:4][CH:3]=1.[Li]CCCC.B(OC)(OC)[O:28]C.OO.Cl>C1COCC1.O.C(O)(=O)C>[F:1][C:2]1[C:3]([OH:28])=[CH:4][C:5]2[CH2:6][CH2:7][CH:8]([CH:13]3[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]3)[CH2:9][C:10]=2[C:11]=1[F:12]
Reactant: COB(OC)OC
Reactant: CCCC1CCC(C2CCc3ccc(F)c(F)c3C2)CC1
Agent: Cl
Agent: OO
Agent: [Li]CCCC
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCC1CCC(C2CCc3cc(O)c(F)c(F)c3C2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
77.0 g (about 0.26 mol) of crude 7,8-difluoro-2-(4-propylcyclohexyl)-1,2,3,4-tetrahydronaphthalene are initially introduced in 500 ml of THF, and 200.0 ml (0.32 mol) of n-BuLi (15% soln. in hexane) are added at −70° C. After 3 h at this temperature, 37.0 ml (0.33 mol) of trimethyl borate are added dropwise, the batch is warmed to 0° C., and 80 ml of dilute acetic acid (about 30%) are added. The mixture is warmed to 30° C., and 70 ml of hydrogen peroxide solution (35%) are carefully added. When the addition is complete, the mixture is stirred at RT for 2 h. Water is added, and the batch is acidified using dil. hydrochloric acid. The solution is extracted a number of times with MTBE, and the combined organic phases are washed successively with water, sat. sodium chloride soln. and ammonium iron(II) sulfate soln. The solution is dried using sodium sulfate and evaporated to dryness. The crude product is purified by column chromatography (SiO2, toluene). The further purification is carried out by crystallisation from n-heptane, giving 3,4-difluoro-6-(4-propylcyclohexyl)-5,6,7,8-tetrahydronaphthalen-2-ol as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[N:9]([CH3:10])[C:8]([NH2:11])=[N:7][CH:6]=1.[C:16]1([CH:22]([CH2:26][CH3:27])[C:23](O)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[N:9]([CH3:10])[C:8]([NH:11][C:23](=[O:24])[CH:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:26][CH3:27])=[N:7][CH:6]=1
Reactant: Cn1c(Cc2ccccc2Cl)cnc1N
Reactant: CCC(C(=O)O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(C(=O)Nc1ncc(Cc2ccccc2Cl)n1C)c1ccccc1
Reaction time: 16 h

Procedure:
5-(2-Chloro-benzyl)-1-methyl-1H-imidazol-2-ylamine (44 mg, 0.20 mmol) and 2-phenyl-butyric acid (33 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (1 mL) containing triethylamine (84.1 μL, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography (13 mg, 0.035 mmol, 18%), ES(-MS m/z calc. 367.2, found 368.1 (M+1)+ Retention time 2.42 minutes.
Reaction SMILES: S([O-])([O-])(=O)=O.[Na+].[Na+].[CH3:8][S:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.S([O-])([O-])(=O)=O.O[NH3+:24].O[NH3+]>>[CH3:8][S:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:24])=[CH:12][CH:11]=1
Reactant: CSc1ccc(C=O)cc1
Reactant: [NH3+]O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: CSc1ccc(C#N)cc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
With stirring (20 rpm), a turbine dryer is charged at room temperature with 4000 parts by weight of anhydrous sodium sulfate, 950 parts by weight of 4-(methylthio)benzaldehyde and 538.4 parts by weight of hydroxylammonium sulfate. Following evacuation to 25 mbar, the mixture is heated to 80° C. and stirred at this temperature for 3 hours. It is subsequently heated at 130° C. and held for 30 minutes at the same pressure. A total of about 240 parts by weight of water are removed by distillation altogether. The distillation of the nitrile is initiated and controlled by reduction of the pressure to 5 mbar and subsequent raising of the jacket temperature to 150° C. 708 parts by weight of 4-(methylthio)benzonitrile are obtained with a purity of over 98% (TLC), and also 18 parts by weight of a mixed fraction essentially consisting of 4-(methylthio)benzonitrile and 4-(methylthio)benzaldehyde. The collected 4-(methylthio)benzonitrile has a melting point of 61°-63° C.